This invention relates to a new class of azole derivatives, methods for their use, and processes for their production. The compounds described herein are useful for the treatment of fungal infections in humans and other mammals. The present invention provides a compound represented by the general formula 
wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, and R1 and R2 are hydrogen, C1-C6 alkyl or C2-C6 alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R1 and R2 taken together with the nitrogen to which they are attached forms a heterocyclic group of the formula 
where R7 is hydrogen, CHO, COR13 or C1-C6 alkyl in which the alkyl group may be optionally interupted by an oxygen atom or NR14 and may be substituted by hydroxy, R8, R9, R10, R11 and R12 are each independently hydrogen, hydroxy, CONH2, or C1-C6 alkyl, said alkyl group being optionally substituted by hydroxy, R13 is C1-C6 alkyl and R14 is hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.
Triazole antifungal compounds are well known in the prior art. Of the several classes known, one particularly potent class contains a tertiary hydroxyl group. For example, U.S. Pat. No. 5,648,372 discloses that (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol has anti-fungal activity. 
The utility of this class of compounds is limited by their low water solubility. One method of addressing this problem was disclosed in European Patent Application 829478, where the water solubility of an azole antifungal agent was increased by attaching a linked amino-acid to the azole portion of the molecule. 
Alternatively, WO 97/28169 discloses that a phosphate moiety can be attached directly to the tertiary hydroxyl portion of the anti-fungal compound, e.g. the compound having the formula 
Examples describing the use of N-N-dialkylaminomethyl benzoate derivatives as prodrugs can be found in H. Bundgaard et al, J. Med. Chem. 32, 2503 (1989); E. Jensen et. al. Int. J. Pharmaceut. 58, 143 (1990); and H. Bundgaard, Drugs of the Future 16, 443 (1991).
It has now been found that triazole anti-fungal compounds containing a secondary or tertiary hydroxyl group, including (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol, may be converted into prodrugs with superior properties to those previously disclosed by attaching an amino-containing moiety via a linking group. Specifically, the invention covers compounds of the formula: 
wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, and R1 and R2 are hydrogen, C1-C6 alkyl or C2-C6 alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R1 and R2 taken together with the nitrogen to which they are attached forms a heterocyclic group of the formula 
where R7 is hydrogen, CHO, COR13 or C1-C6 alkyl in which the alkyl chain may be optionally interupted by either an oxygen atom or NR14 and may be substituted by a hydroxy group, R8, R9, R10, R11 and R12 are each independently hydrogen, hydroxy, CONH2 or C1-C6 alkyl, said R8, R9, R10, R11 or R12 alkyl group being optionally substituted by hydroxy, R13 is C1-C6 alkyl and R14 is hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
The various methylamine substituents of formula I may be attached in either an ortho, meta, or para relationship to the ester substituent, with the preferred attachment being either meta or para.
In a preferred embodiment A can be 
wherein R3 represents phenyl substituted by one or more (preferably 1-3) halogen atoms;
R4 represents H or CH3;
R5 represents H, or taken together with R4 may represent xe2x95x90CH2;
R6 represents a 5- or 6 membered nitrogen containing ring which may be optionally substituted by one or more groups selected from halogen, xe2x95x90O, phenyl substituted by one or more groups selected from CN, (C6H4)xe2x80x94OCH2CF2CHF2 and CHxe2x95x90CHxe2x80x94(C6H4)xe2x80x94OCH2CF2CHF2, or phenyl substituted by one or more groups selected from halogen and methylpyrazolyl.
Nitrogen containing heterocycles which R6 may represent include triazolyl, pyrimidinyl, and thiazolyl.
Specific examples of A include, but are not limited to, the following: 
In addition to the application of the present invention to structures containing a tertiary alcohol, it should also be understood that this discovery can be applied to anti-fungal agents which contain secondary alcohols. Some examples include, but are not limited to, the following: 
Representative R1, R2 and n values are shown below: 
(where A represents the non-hydroxy portion of a triazole anti-fungal compound of the type containing a tertiary or secondary hydroxyl group)
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein is intended to include the non-toxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like.
The term xe2x80x9chalogenxe2x80x9d includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro, and most preferably fluoro.
The aliphatic xe2x80x9calkylxe2x80x9d and xe2x80x9calkenylxe2x80x9d groups may be straight or branched chains having the specified number of carbon atoms, e.g. in the case of C1-C6 alkyl, the alkyl group may have from 1 to 6 carbon atoms.